Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; also known as CD39), works in concert with 5′-nucleotidase (also known as ecto-5′-nucleotidase or CD73), to modulate the duration, magnitude and chemical nature of purinergic signals by hydrolyzing extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine monophosphate (AMP) (by CD39) and AMP to adenosine (by CD73). Immune cell-expressed P1 receptors (G protein-coupled receptors) and P2 receptors a are activated by adenosine and ATP, respectively and mediate the immunomodulatory effect of purines. ATP-driven effects are proinflammatory, while adenosine promotes anti-inflammatory effects in immune cells. Both CD39 and CD73 are highly expressed on regulatory T cells (Tregs), which are a CD4+ subpopulation that help maintain immune system homeostasis. Expression of both CD39 and CD73 is upregulated on Tregs upon activation. The ATP-metabolizing activity appears to be critical for the immunosuppressive activity of Tregs. The inhibitory control by Treg-derived adenosine is mediated by the engagement of A2A P1 receptors on effector T cells, resulting in reduction of proinflammatory cytokines and chemokines
Increased adenosine levels mediated by CD39 and CD73 generate an immunosuppressive environment which promotes the development and progression of cancer. CD39 and CD73 participates in the evasion of tumors by the immune system by inhibiting the activation, clonal expansion and homing of tumor-specific helper T (Th) cells and cytotoxic T cells (CTL), by impairing the cytolytic effector T cells.
Myeloid-derived suppressor cells (MDSCs) also promote tumor growth by a CD39-mediated mechanism. For example, CD39 expression is elevated on MDSCs isolated from cancer patients and these cells display inhibitory effects against anti-tumor T cells, as compared with MDSCs from healthy donors.
In addition, Tregs from CD39 knockout mice are constitutively activated, proliferate excessively, and have lost their suppressive function. Melanoma growth, as well as lung metastases, was also markedly decreased in knockout mice as compared to wild-type mice, with severe defects in angiogenesis also observed.
There is a need understand the role of CD39 in diseases, including cancers, and the development of therapies directed against CD39.